Autoimmune sensorineural hearing loss (ASNHL) is the most common cause of sudden hearing loss in adults and is typically characterized by a bilateral, rapidly progressive hearing deficit that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. We have recently shown that ASNHL patients have increased frequencies of inner ear-specific interferon-gamma- producing T cells in their peripheral blood compared to age- and sex-matched control subjects. Thus, inner ear-specific proinflammatory T cells appear to be implicated in the etiopathogenesis of ASNHL. Moreover, we have found that a targeted T cell response to defined inner ear specific peptides is capable of mediating hearing loss in SWXJ mice. In the current application, our working hypothesis is that ASNHL is at least in part a T cell-mediated organ-specific autoimmune disorder of the inner ear. Our proposed experiments are designed to identify and characterize the hierarchy of inner ear-specific target antigens and T cell repertoires involved in the development, progression, and immunoregulation of both human ASNHL and its murine counterpart. The significance of ASNHL as opposed to other forms of hearing loss resides in its potential for medical intervention. We believe that our proposed experimental design will substantially advance our understanding of ASNHL and thereby provide a basis for developing contemporary immunomodulatory therapies that may dramatically change and improve treatment of this debilitating hearing disorder. [unreadable] [unreadable]